Despite the AIDS epidemic, in South Africa cardiovascular disease (CVD) is the main cause of death in relatively young people (35-44 years). It has been suggested that the dramatic surge in CVD rates may be due to accelerated urbanization and associated lifestyle changes (e.g. increased fat consumption and sedentary lifestyle). These alarming projections together with the limited research capacity within South Africa in the CVD field, have led to Dr. Essop's research team to focus on the role of a high fat diet on altered cardiac metabolism in the pathogenesis of CVD. In particular, the focus of this project is to ascertain whether elevated cardiac fatty acid metabolism contributes to the onset of heart failure. An emerging hypothesis suggests that perturbations in cardiac metabolism plays an integral role in the development of cardiac hypertrophy and the transition to heart failure. In support of these concepts, a recent study demonstrated a positive correlation between increased plasma free fatty acid (FFA) levels and the expression of cardiac-enriched uncoupling proteins (UCPs), specifically UCP2 and UCP3, in heart failure patients. In light of this, we hypothesize that heart failure is a hyperadrenergic state and that contractile dysfunction in failing hearts is due to reduced cardiac efficiency as a consequence of elevated FA utilization and FA-induced uncoupling of mitochondria) oxidative phosphorylation. To test this hypothesis, a well- characterized hypoxia-induced model of adaptive right ventricular hypertrophy developed by Dr. Essop will be employed. Specific Aims of this FIRCA Grant are to: 1) Assess effects of increased cardiac mitochondria! fatty acid oxidation (induced by high fat feeding) on right ventricular cardiac output and efficiency of mitochondria) ATP production, and 2) Determine whether detrimental effects on cardiac output and mitochondria! energy production as a result of increased mitochondria! fatty acid oxidation can be reversed by administration of specific therapeutic agents inhibiting cardiac mitochondria! FA uptake [unreadable] [unreadable] [unreadable]